TRP channels and the regulation of vascular permeability: new insights from the lung microvasculature.
TRP channels and the regulation of vascular permeability: new insights from the lung microvasculature.
复制标题
TRP 通道和血管通透性调节：来自肺微脉管系统的新见解。
DOI：
10.1161/01.res.0000249618.51440.c6
复制
发表时间：
2006
影响因子：
20.1
通讯作者：
Glass,CatherineA
中科院分区：
文献类型：
--
作者：
Curry,Fitz-RoyE;Glass,CatherineA
最广泛认可的引发炎症反应的机制之一是钙进入内皮细胞。1-3近年来的研究表明，有多种机制决定钙离子流入内皮细胞（包括配体门控钙通道、钙池操纵钙通道和机械敏感性钙通道），并且这些不同的机制优先分布在不同的内皮细胞之间。这些观察结果对调节血管张力和重塑的功能后果开始被理解4，5，但这不是完整器官中内皮屏障功能调节的情况。在这个问题上，阿尔瓦雷斯等描述了肺节段性血管通透性调节的一个重要例子。6他们证明了钙通道家族的香草酸亚类的激活，称为瞬时受体电位通道，（在这种情况下是TRPV 4通道）优先增加肺微脉管系统的初级气体交换隔膜区的内皮层和上皮层的渗透性，而其它钙通道，例如储存操纵的钙通道，增加了主要气体交换区域（所谓的肺泡外区域）外部的渗透性。这些都是重要的观察结果，因为中隔屏障处内皮的破坏比肺泡外血管的破坏更可能引起肺泡灌洗和损害气体交换。到目前为止，已经发现了至少28种哺乳动物TRP异构体。TRP通道已被细分为3个主要类别，TRPC（典型），TRPM（melastatin）和TRPV（vanilloid），尽管最近也提出了其他类别（TRPP [多囊蛋白]，TRPML [粘磷脂]和TRPA [锚蛋白]）。通道的一般特征是它们仅通过非常小的电流（钙离子通量）并且充当钙进入的被动传导途径，即，它们不是电压门控的。因此，钙通量取决于通道表达的局部密度和驱动钙进入细胞的电化学驱动力。特别地，内皮细胞膜的超极化通过增加带正电荷的离子如钙的电驱动力来增强钙进入。例如，当TRP通道在钙调节的钾通道附近被激活时，它们也可以使膜过度膨胀并通过所有开放的钙通道放大钙内流。如最近的综述所述，TRP通道在血管中具有许多功能4，包括调节血管张力（TRPC 4、TRPV 1、TRPV 4）、血管生成（TRPM 6和TRPM 7）、血管重塑（TRPC 4）、氧化应激诱导的反应（TRPC 3、TRPC 4、TRPM 2）和机械感应（TRPV 4）。TRP通道也涉及血管通透性的调节，包括TRPC 1、TRPC 4、TRPC 6和TRPV 1。4由于此时可用的TRP通道的特异性拮抗剂相对较少，因此可能难以鉴定哪个TRP通道参与给定的信号传导事件。Alvarez等人使用了几种策略来区分肺标本中的TRP通道。如下文所讨论的，这些策略中的任何一种都存在置信度的局限性，但本文的优势在于，它关注了几个会聚主题，这些主题对于进一步研究肺中液体蓄积的钙依赖性调节非常重要。Alvarez等人使用的策略包括TRPV 4表达的免疫组织化学定位，局部断裂的光镜和电镜观察。
One of the most widely recognized mechanisms to initiate an inflammatory response is calcium entry into endothelial cells. 1–3 Recent investigations have demonstrated that there are multiple mechanisms which determine calcium flux into endothelial cells (including ligand gated calcium channels, store operated calcium channels and mechanosensitive channels), and that these different mechanisms are preferentially distributed between different endothelial cells. The functional consequences of these observations for regulation of vascular tone and remodeling are beginning to be understood4, 5 but this is not the case for the regulation of endothelial barrier function in intact organs. In this issue Alvarez et al describe an important example of segmental vascular permeability regulation in lung. 6 They demonstrate that activation of the vanilloid subset of the family of calcium channels known as transient receptor potential channels (in this case the TRPV4 channels) preferentially increased the permeability of the endothelial and epithelial layers of the primary gas exchanging septal regions of the lung microvasculature whereas other calcium channels, such as the store operated calcium channels, increased permeability outside the primary gas exchange regions (so called extra-alveolar regions). These are important observations because disruption of the endothelium at the septal barrier is more likely to cause alveolar flooding and impair gas exchange than disruption in extraalveolar vessels. So far at least 28 mammalian TRP isoforms have been discovered. TRP channels have been subdivided into 3 main classes, TRPC (canonical), TRPM (melastatin), and TRPV (vanilloid) although more recently other classes have also been proposed (TRPP [polycystin], TRPML [mucolipin], and TRPA [ankyrin]). 4, 7 A general feature of the channels is that they pass only very small currents (calcium ion flux) and act as passive conductance pathways for calcium entry, ie, they are not voltage gated. Thus the calcium flux depends on the local density of channel expression and the electrochemical driving force driving calcium into the cell. In particular hyperpolarization of the endothelial cell membrane potentiates calcium entry by increasing the electrical driving force for positively charged ions such as calcium. For example, when TRP channels are activated close to calcium regulated potassium channels, they may also hyperpolarize the membrane and amplify calcium influx through all open calcium channels. As described in recent reviews, TRP channels have many functions in the vasculature4 including the regulation of vascular tone (TRPC4, TRPV1, TRPV4), angiogenesis (TRPM6 and TRPM7), vascular remodeling (TRPC4), oxidative stress-induced responses (TRPC3, TRPC4, TRPM2) and mechanosensing (TRPV4). TRP channels have also been implicated in the regulation of vascular permeability including TRPC1, TRPC4, TRPC6, and TRPV1. 4 With relatively few specific antagonists for the TRP channels available at this time, it can be difficult to identify which TRP channel is involved in a given signaling event. Alvarez et al have used several strategies to distinguish the TRP channels in their lung preparation. As discussed below there are limitations to the confidence that can be placed in any one of these strategies, but a strength of the present article is that it focuses attention of several converging themes that are important for further investigations of calcium dependent regulation of fluid accumulation in the lung. The strategies used by Alvarez et al include immunohistochemical localization of TRPV4 expression, light and electron microscopy of localized breaks …